Adoptive transfer of immunity to HBV in liver transplant patients:A step forward toward the proof of concept for therapeutic vaccination or a transient immunologic phenomenon?

Abstract

In this issue of the journal, Dr. Luo and co-workers have identified intra-graft hepatitis B virus (HBV) specific lymphocytes in HBV immune liver donors, (most of whom were live donors) and correlated their findings with the liver transplant recipients' humoral immune responses to HBsAg. 1 HBV specific T and B cells were identified in 59% and 28% of liver grafts respectively in 32 donors. After liver transplantation, almost half of the transplanted patients with chronic HBV developed anti-HBs seroconversion which correlated with the number of donor graft derived HBsAg specific T cells. The investigators suggest that these donor derived HBV specific lymphocyte may be the vehicle through which adoptive transfer of immunity is transferred from HBV immune donors to liver graft recipients with persistent HBV infection. This important study provides for the first time evidence on HBV specificity of intrahepatic lymphocytes isolated from human liver grafts and transplanted to patients with chronic HBV infection. The study sheds further light on the presumed mechanism involved in adoptive transfer of immunity in the setting of parenchymatous organ transplantation. Furthermore, it may take us one step forward in the quest for developing new means for the so called "vaccinotherapy" for controlling persistent HBV infection.Analysis of the reported data requires a short look back on the progress already achieved in this exciting area of clinical research.Patients with acute HBV infection who recover spontaneously are able to clear HBV from the circulation by mounting an effective innate, cellular and humoral immune response leading to long-term, usually life-long immunity. 2,3 Some patients may clear the virus from the circulation, but remain with occult HBV infection with covalently closed circular (ccc) HBV-DNA "hiding" in hepatocytes. Yet, these recovered patients rarely reactivate HBV infection in the presence of an intact immune system and "immune memory" which serve as a gate keeper for prevention or suppression of viral replication and its consequences. In contrast, patients with persistent HBV infection are often tolerant to HBV and unable to mount an effective cellular and humoral immune response toward nucleocapsid and envelope proteins of the virus. This is also true for HBV patients undergoing liver transplantation who in addition to this immunologic defect are also immune suppressed by pharmacologic agents for prevention of graft rejection.Current strategies for protection of HBV liver transplant recipients at risk include lifelong monotherapy with hepatitis B immune globulin (HBIG) or a nucleoside analogue or combination therapy using the two agents simultaneously and indefinitely or at least for a defined period, followed by life-long monotherapy. 4 These strategies, which also include pre-transplant suppression of HBV viral load, have led to an impressive success rate in prevention of HBV graft re-infection in about 90% of patients treated with combination therapy. However, although the risk of graft re-infec...

Hepatitis B and liver transplantation: 2008 update

“…Studies in several animal models and human trials have already demonstrated that immunity to HBV can be adoptively transferred, even in the setting of organ transplantation [120][121][122][123]. It is yet unclear if the adoptively transferred immunity to HBV is generated by engrafted donor-derived HBV specific lymphocytes or through chimerism between donor and host lymphocytes [123].…”

Effects of Dendritic Cells from Hepatitis B Virus Transgenic Mice-Stimulated Autologous Lymphocytes on Hepatitis B Virus Replication: A Study on the Impact of Specific Sensitized Effector Cells on In Vitro Virus Replication

“…Currently HBV cccDNA is considered to be immune eliminated in the body by: (a) cell lysis that eliminates the infected hepatocytes, with the HBV phagocytized by macrophages or combined with anti-HBs antibodies to form immune complexes themselves phagocytized by macrophages and excreted in the urine, with the damaged hepatocytes replaced by regenerated cells; and (b) clearance mediated by Th1 cytokine-dependent non-cytolytic mechanisms, such as interferon, tumor necrosis factor, and interleukin-2, which mediate non-cytolytic mechanisms to eliminate HBV cccDNA in the nuclei or block the synthesis of new HBV cccDNA (10,27). It has also been reported that HBV elimination was achieved by adoptive transfer of immunity from a donor to the liver transplant recipient (26).…”

The difficulties of managing severe hepatitis B virus reactivation

“…Conversely, there have been fewer reports in autologous bone marrow transplantation. Several studies have provided further evidence that immunization of donors may induce HBV immunity in recipients within several days to weeks after transplantation (29).…”